Pyridine compounds



States PYRIDINE COMPOUNDS August Hans Lutz and Otto Schnider, Basel,Switzerland, assignors to Holfrnann-La Roche Inc., Nutley, N. 5., acorporation of New Jersey No Drawing. Application October 28, 1957Serial No. 692,526

Claims priority, application Switzerland November 28, 1956 8 Claims.(Cl. 260-296) R and R in the above formula each represents an alkyl oralkenyl group.

The compounds of Formula I may be hydrogenated to obtain3,3-disubstituted-2-amino-4-oxo3,4,5,6-tetrahydropyridine bases whichmay be represented by the following structural formula:

(II) R and R in Formula II each represents an alkyl group.

The compounds of both Formula-I and Formula II form acid addition saltsand, these salts. are also within the scope of the invention. Thecompounds of this invention are useful as sedatives .and hypnotics. Theymay be administered orally or parenterally, preferably by in corporatingtherapeutic doses in tablets or in liquid preparations according toconventional procedures.

R and R in the above formulae represent alkyl or alkenyl groups such asmethyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, allyl, isobutenyl,etc. R and R represent similar alkyl groups. The groups represented by Rand R or R and R in a given compound may be the same, that is, bothsubstituents may be identical alkyl groups or identical alkenyl groups,or they may be mixed, that is, two dilferent alkyl groups or one alkylgroup and one alkenyl group, as the case may be. According to apreferred modification, the alkyl and/or alkenyl groups'represented byR, and R or R and R together have a ate 'acetonitrile.

total of 2 to 10 carbon atoms. Most preferred are lower alkyl or loweralkenyl groups.

For convenience the groups represented by R and R or R and R in thecompounds of Formulae I and II above and the same substituents in theintermediates from which they are derived are sometimes hereinafterreferred to as dialkyl groups, but this term is an abbreviated formintended to signify the alkyl and alkenyl groups defined in thepreceding paragraph.

The compounds of this invention may be produced in the following manner.A monoalkylor monoalkenylacetoacetonitrile may be alkylated, for examplewith an alkyl halide or alkenyl halide, to obtain a,a-dialkyl-aceto- Thelast named compound is treated with a formic acid ester, such as methylformate, and with an alkaline condensation agent, such as sodiummethylate, then with ammonia to obtain 1,1-dialkyl-l-cyano-2-oxo-4-amino-3-butene. The butene compound is cyclized with an alkalialcoholate, such as sodium methylate, preferably in methanol, to produce2-amino-3,3-dialkyl-4-oxo- 3,4-dihydropyridine. The last named compoundis then catalytically hydrogenated to obtain 2-amino-3,3-dialkyl-4-oxo-3,4,5,6-tetrahydropyridine.

Alternatively, a monoalkyl-acetoacetamide may be alkylated and thea,a-dialkyl-acetoacetamide thus obtained is dehydrated with thionylchloride or phosphorus oxychloride to obtaina,a-dialkyl-acetoacetonitrile which is then further treated as describedabove.

The cyclization of the 1,l-dialkyl-1-cyano-2-oxo-4- amino-3-butene ispreferably effected by the action of an alkali metal alcoholate in thepresence of the corresponding alcohol at a slightly elevatedtemperature. For example, 1,l-dialkyl-l-cyano-2-oxo-4-amino-3-butene maybe dissolved in methanol, treated with sodium methylate and then heatedto boiling under reflux. The 3,3-dialkyl-2amino-4,-oxo-3,4-dihydropyridine thus formed may be obtained incrystalline form by partially distilling off the alcohol and addingwater.

The 3,3 disubstituted 2 amino 4 oxo 3,4 dihydropyridine may, if desired,be reduced to the corresponding 3,3-disubstituted-2-amino-4-oxo-3,4,5,6-tetrahydropyridine. This may be efiected, forexample, by catalytically hydrogenating the base or its salt, preferablyin the presence of a noble metal catalyst, e. g. finely dividedpalladium. By this procedure unsaturated substituents in the 3-positionare hydrogenated to saturated groups. The3,3-disubstituted-2-amino-4-oxo-3,4,5,6- tetrahydropyridines produced inthis manner may be isolated by separating the catalyst from thehydrogenation reaction mixture and evaporating the solvent.

The compounds are strongly basic substances and form acid addition saltswith various organic and inorganic acids such as acetic acid, tartaricacid, salicylic acid, the hydrohalic acids, e. g. hydrochloric acid andhydrobromic acid, and other mineral acids such as sulfuric acid,phosphoric acid, etc. Pharmaceutically acceptable acid addition saltsconstitute a preferred group. The acid addition salts are produced bytreating the base with the appropriate acid, preferably in a solvent, e.g. hydrochloric acid in alcohol.

Although the foregoing discussion speaks in terms of only one tautomericform of the intermediates and final 'methylate.

products represented by the above formulae, the compounds may exist inother tautomeric forms which are also within the scope of the invention.Other tautomeric forms of the compounds may, for example, be formulatedas 3,3-disubstituted-2-imino-4-oxo-1,2,3,4-tetrahydropyridine and3,3-disubstituted-Z-imino-4-oxopiperidine, respectively.

The following examples are illustrative of the invention. Alltemperatures are in degrees centigrade.

EXAMPLE 1 100 g. of diethyl-acetoacetami-de .were heatedwith-100 g. ofthionyl chloride to boiling under reflux for mlnutes, then freed in--vacuo-from most of the thionyl chloride and poured into a mixtureofice and soda solution. The mixture was extracted with ether and theether solution, after drying over-sodium sulfate, was distilled. Atfirst the ether'evaporated v.andthe the oc,adiethyl-acetoacetonitrileproduced distilled over at 73- 76/ 13 mm.

770 .g. of can:-diethyl-acetoacetonitrile and 500 g. of formic acidmethyl ester were dissolved in 2,000-cc.'of toluene and treatedportionwise with 316-g.-of sodium The reaction mixture was cooled asrequired so thatthetemperaturedid notexceed 27. At-the-end of thereaction, ice water was added, the organic phase was separated andextracted with three 100 cc. portions of 3 N sodiumhydroxide. Thecombined aqueous extracts were treated with 390 g. of ammonium chloride,70 cc. of aqueous ammonia and 1,000 cc. of benzene and warmed for 75minutes at 6070 withvigorous stirring. After cooling, thebenzene layerwas separated and the aqueous phase was extracted twice with -150-cc.portions of benzene. After evaporating the solventthere remained anoil-which quickly solidified. The -1,l-diethyl-1-cyano-2-oxo-4-amino-3-butene obtained-in this manner boiled-at 137-145-/O.1 mm. After dissolving-and crystallizing from petroleum ether, thelight yellow crystals melted at 67.

835 g. of 1,1-diethyl-1-cyano-2-oxo-.4-amino-3-butene were dissolved in700 cc. of-warm methanol and treated with 270 g. of sodium methylatewith occasional cooling. The dark red colored solution was'heated to.reflux for 10 minutes and then concentratedto about its volume. Theconcentrate was cooled with ice water and treated with 1,500 cc. of icewater while stirring vigorously. The2-amino-3,3-diethyl-4-oxo-3,4-dihydropyridine 'crystallized in yellowcrystals which were difiicultly soluble in water. To complete thecrystallization, an additional portion of methanol was evaporatedfromthe cold soluhydrogen, the hydrogenation came to an end. The catalystwas separated from the solution which was then concentrated and treatedwith dry ether. The colorless crystalline hydrochloride of 2 amino 3,3diethyl 4 oxo- 3,4,5,6-tetrahydropyridine melted at 263-264.

EXAMPLE 2 100 g. of isopropyl-acetoacetamide were dissolved in i 100 g.of phosphorus oxychloride, quickly warmed to 100 and-pouredout ontoiceand potassium carbonate solution. The reaction mixture was extractedwith ether and the ether solution, after drying with sodium sulfate, wasdistilled under water vacuum. At first, the ether evaporated, then theisopropyl-acetoacetonitrile distilled over at 7880/10 mm.

300 cc. of boiling diethyl carbonate was treated first with 43 g. ofsodium methylate and then with g. of isopropyl-acetoacetonitrile.Approximately 50 cc. of the mixture was then distilled off. To thesuspension of the sodium salt thus formed, g. of allyl bromide wereadded. The reaction mixture was refluxed with stirring for a short time,cooled, treated with ice water, separated from the aqueous phase anddistilled under water vacuum. The a-allyl-a-isopropyl-acetoacetonitrilethus produced boiled at 87-89/1l mm.

A mixture of 112g. of a-allyl-a-isopropyl-acetoacetonitrile, 61 g. offormic acid methyl ester and 200 cc. of benzene were poured into asuspension of 16.3 g. of finely divided sodium in 200 cc. of benzene andstirred for 16 hours. By means-of occasional cooling the temperaturewithin the flask was maintained below 28. The sodium salt of1-allyl-.l-cyano-1-isopropyl-2-oxo-4-hydroxy-3- butene thus formed andwater were brought into solution and the phases were separated from eachother. The organic phase was washed with approximately 30 cc. of

.3 N sodium hydroxide, the combined aqueous extracts were treated with300 cc. of benzene, 75 g. of ammonium chloride and 20cc. of concentratedammonia and the mixture was intensively stirred for 1% hours at 70. Thebenzene solution, containing l-allyl-l-cyano-l-isopropyl-2-oxo-4-amino-3-butene, was separated, dried and concentrated. After theevaporation the residue spontaneously solidified, M. P. 73-74.

.100 g. of l-allyl-lrcyano-1:isopropyl-2-oxo-4-amino-3- butene wereintroducedinto a solution of 18 g. of sodium and 250 cc. of methanolwith stirring. The mixture was refluxed for hour. Then approximately 100cc. of methanol were permitted to distill off under reduced pressure,the dark colored solution was cooled and treated with 400 cc. of icewater whereupon 2-amino-3-allyl-3- isopropyl-4-oxo-3,4-dihydropyridineprecipitated as yellow colored crystals. The melting point of the base,recrystallized from methanol, was 162163.

The hydrochloride of 2-amino-3-allyl-3-is0propyl-4-oxo-3,4-dihydropyridine, P. 178, was produced by treatingthe base withhydrochloric acid in alcohol as described in Examplel.

2 amino 3 allyl 3 isopropyl 4 0x0 3,4 dihydropyridine was dissolved inmethanol, treated with 5% palladium charcoal and agitated at roomtemperature with hydrogen. After one mol of hydrogen was ab sorbed, thehydrogenation was stopped, the catalyst was filtered off and themethanol solution was concentrated.

The residue, 2-amino-3-isopropyl-3-n-propyl-4-oxo-3,4-di- Vhydropyridine, melted at l90191 after recrystallization from methanol. 7

The hydrochloride of 2-amino-3-isopropyl-3-n-propyl-4-oxo-3,4-dihydropyridine was produced by the method .described above,M. P. 179.

amino 3 isopropyl 3 n propyl 4- 0X0 3,45,6-

tetrahydropyridine crystallized in colorless needles, M. P. 182.

Additional compounds represented by Formulae-I and II above and saltsthereof were synthesized according to the method of Example 2. Themelting point or boiling point of the intermediates and final productsobtained are wherein the two alkyl groups together have a total of 2 setforth in the following table. to 10 carbon atoms.

Table R1 R: A B

Base, H01, Base, H01, M P M. P. M. P. M

B. B. P44 161-172- 149 B. B. P.o.o5 152 140 B. 011 143 B. B. P. 0.05 150116 B. M. P. 74-75"- 212 B. M. P. 114.- 225 Is butenyL-" B. 011 175 ylAlly] B. on 146 IsopropyL-.. n-Propyl B. P. 89-91" 191 A MR-a-R7-8.(!Bt08.09t0111tti18. B l-Ri-l-R -1-cyano-2-oxo-4-amino-3 butene.C=3-R -3-Rn-2-a1nino-4-oxo-3,4-dihydropyridine. D=3-R -3-R-2-amino-4-oxo-3,4,5,6-tetrahydropyridine. We claim: 3. A compoundhaving the formula 1. A member of the group consisting of bases havingthe formula 0 0 alkenyl\ alkenyl-O on Rr-O CH HgN- H HsN-( H and whereinthe two alkenyl groups together have a total of O 2 to 10 carbon atoms.4. A compound having the formula Rs C R| O/ \ZH! E HgN- Hg alkyl alky1 Gom wherein R and R each represents a member of the group HIN- H:consisting of alkyl and alkenyl, and R and R each represents alkyl, saidgroups represented by R and R and by R and R having together a total of2 to 10 carbon atoms in a given compound, wherein the two alkyl groupstogether have a total of 2 to 10 carbon atoms. and pharmaceuticallyacceptable acid addition salts of 5. 2 amino 3,3 diethyl 4 oxo 3,4,5,6tetrahysaid bases. dropyridine.

2. A compound having the formula 6. 2 amino 3,3 di n propyl 4 0x0 3,4di.

0 hydropyridine. alkyl I5 7. 2 amino 3,3 diallyl 4 oxo 3,4dihydropyridine. alkyl-C CH 8. 2 amino 3,3 di n propyl 4 oxo 3,4,5,6- Htetrahydropyridine.

No references

1. A MEMBER OF THE GROUP CONSISTING OF BASES HAVING THE FORMULA